Method and composition for transdermal drug delivery

ABSTRACT

The invention is directed to a transdermal drug delivery composition which includes at least one physiologically active agent; and at least one volatile solvent; and at least one viscosity modulating agent. The invention extends to methods of administering such a composition to a subject and treatment of subjects using the composition.

FIELD OF THE INVENTION

The present invention relates to a method and composition fortransdermal delivery of a physiologically active agent. It hasparticular but not exclusive application to the delivery of an agent inareas prone to perspiration.

BACKGROUND OF THE INVENTION

Efficient transdermal delivery of a physiologically active agent offersseveral clinical and patient advantages in treatment of disease.

Drug delivery by injection is traditionally the quickest route ofadministration to the systemic circulation, however the duration ofaction of is often short lived and the mode of delivery is invasive andpainful. Transdermal drug delivery is receiving increased attention dueto the ability of the administration regime to provide a controlledroute for the release of an active agent to the systemic circulation.

However, transdermal drug delivery is complicated by the fact that theskin behaves as a natural barrier. As a result, the success oftransdermal delivery system often relies on the ability of a compositionto be able to penetrate the stratum corneum of the skin and therebytransport an active agent across the skin.

Problems with transdermal delivery arise particularly in cases where adrug is slow to be absorbed through the skin or where a relative highdose of drug needs to be absorbed. In these circumstances it is oftennecessary to apply a transdermal composition to a large area of skin inorder to achieve the required dose.

One example of this problem is encountered in the administration ofandrogens such as testosterone. Recent estimates show that approximately13 million men in the United States experience testosterone deficiencyand less than 10% receive treatment for the condition. The daily doserequired to maintain testosterone levels within the normal range isrelatively high (typically 5-10 mg/day), thus it provides a challengefor transdermal delivery. Similar problems occur with progesterone. Thepreviously used topical administration of testosterone, for example intreatment of hypogonadism, requires application of gel or cream to awide area of the body and that the area of application remains covered.Application of composition over a wide area severely increases the riskof transfer from patient to partner or child, thus persons such asfamily members may be subjected to accidental dosing of the drug. Thiscan have serious consequences.

Transdermal administration of some drugs may also be accompanied byundesirable side effects. For example, testosterone is responsible forincreasing perspiration and producing perspiration related odour in thepresence of the enzyme 5-alpha-reductase which converts testosterone todihydrotestosterone (DHT). Scrotal skin has a relatively high level of5-alpha-reductase and continuous trans-scrotal delivery of testosteroneproduces levels of DHT and DHT/testosterone ratios 4 to 5 fold greaterthan normal. Such abnormal levels and ratios may give rise toundesirable side effects.

Problems also arise with the location of application, and side effectsassociated with the location. Ahmed, S. R., et al. (J Clin EndocrinolMetab (1988) 66:546-557) and Findlay, J. C. (J Clin Endocrinol Metab(1989) 68:369-373) report that the 60 cm² ALZA trans-scrotal systemdelivers about 3.7 mg/day and produces low-normal testosterone levels inhypogonadal men. Such dosages are believed to be somewhat less than theamount needed to mimic endogenous production (5-10 mg/day).

Trans-scrotal delivery of testosterone is also associated with highdihydrotestosterone (DHT) and DHT/testosterone ratio levels and does notprovide a level of testosterone delivery that mimics endogenousproduction. Further, scrotal skin is sensitive and as noted above,limited in area, which may result in discomfort and poor patientacceptance of this modality of delivery.

Many transdermal compositions utilise penetration enhancers to assistdelivery of the pharmaceutical active across the skin. Increasedcutaneous blood flow and subsequent heat production is also reported toassist. U.S. Pat. No. 6,743,448 describes a topical testosteroneformulation comprising arginine which is said to facilitate theproduction of nitrous oxide and enhance vasodilation.

However locally induced vasodilation and subsequent heating,particularly in areas having increased cutaneous blood flow such as theaxilla is likely to cause excess perspiration and discomfort, due to theincreased number of sweat glands present in such areas. This can beproblematic for the subject on the basis that transdermal delivery ofsome pharmaceutical actives may be hindered by the use ofantiperspirants and/or deodorants. This is undesirable because deliverymay be compromised because of perspiration, resulting in inconsistentdelivery and/or patient acceptability and compliance is hindered byinstructions not to use antiperspirant or deodorant with drug deliverythat promotes perspiration.

There is therefore a need for a method and composition for transdermaladministration which provides rapid, consistent delivery and allows thearea of application to be minimised, as well as being convenient forsubjects to use desirably with reduced side effects to subjects andothers with whom they come in contact.

SUMMARY OF THE INVENTION

In accordance with one aspect, the invention provides a transdermal drugdelivery composition which includes (i) at least one physiologicallyactive agent; and (ii) at least one volatile solvent; and (iii) at leastone viscosity modulating agent. In some embodiments, the compositionfurther comprises a penetration enhancer. In some embodiments, theviscosity modulating agent is a gelling or thickening agent. In someembodiments, the solvent is a lower alkyl alcohol or a mixture of suchalcohols. In some embodiments, the penetration enhancer is one or amixture of octyl dimethyl-para-aminobenzoate, octylpara-methoxycinnamate and octisalate. In some embodiments, thecomposition further comprises an antiperspirant and/or a deodorant.

In accordance with another aspect, the invention provides a method ofdelivering an active agent systemically to a patient by application ofthe active agent to one or more axilla. In some embodiments,administration is essentially only to the axilla. In some embodiments,an antiperspirant and/or a deodorant is applied at about the same timeas a composition comprising the active agent.

In accordance with another aspect, the invention provides a method oftreatment of testosterone deficiency of a subject comprising delivery ofan androgenic compound according to the method describe above, in whichthe active agent is the androgenic compound.

In accordance with another aspect, the invention provides a method ofdelivering an agent systemically to a patient by application of theactive agent with a volatile solvent to one or more axilla. In someembodiments, the active agent is in a transdermal drug deliverycomposition as described above.

In accordance with another aspect, the invention provides a method oftransdermal testosterone delivery to a subject comprising topicallyapplying to an area of skin of a subject a transdermal compositioncomprising (i) an androgenic compound; and (ii) a volatile carrier; and(iii) at least one dermal penetration enhancer; and (iv) at least oneviscosity modulating agent. In some embodiments, the androgenic compoundis testosterone or a derivative thereof. In some embodiments, the areaof skin is the axilla and testosterone is delivered resulting in a bloodlevel of at least a predetermined amount.

BRIEF DESCRIPTION OF THE DRAWINGS

In the drawings:

FIG. 1 is a graph showing the variation in blood level of testosteronewith time after transdermal application;

FIG. 2 is a graph of testosterone permeation profiles obtained afterapplication of a deodorant spray to a composition according to oneembodiment of the invention;

FIG. 3 is a graph of testosterone permeation profiles obtained afterapplication of ethanol (3 μL) to the same embodiment of the invention asin FIG. 2;

FIG. 4 is a graph of the testosterone permeation profiles obtained fromthe application of a different embodiment of the invention compared withapplication of a control.

FIG. 5 is a graph of the estradiol permeation profile obtained from theapplication of another embodiment of the invention compared withapplication of a control.

DETAILED DESCRIPTION

The applicant has developed a method and a composition for transdermaladministration which allows rapid delivery of active agents and reducesthe risk of undesirable side effects in a patient. The delivery is“rapid” in the sense that little time of the patient is required. Forexample, in one embodiment, the transdermal composition is dry within 3minutes. Pharmacodynamically, delivery of the active is substantially“steady-state”, once a reservoir of the active is established in theskin. The reservoir is maintained (ie, “topped-up”) by daily doses ofthe composition. Steady-state is the practical description of thedelivery profile—there is some, but surprisingly minor, variation indelivery rates between doses. The invention therefore provides a methodof administration which allows rapid delivery of active agents andminimises the risk of side effects in a patient.

The applicant has surprisingly observed that the transdermal compositionof the current invention has antiperspirant and/or deodorant properties.The composition therefore allows the active agent to be rapidlydelivered whilst also enabling perspiration and/or odour to be reduced.The use of the invention thus permits use of areas such as the axillafor transdermal drug delivery without patient inconvenience of not usingnormal antiperspirant/deodorant products (important for patientcompliance) which may otherwise interfere with delivery of the active.

As such, there is provided a transdermal drug delivery composition whichincludes at least one physiologically active agent; and at least onevolatile solvent; and at least one viscosity modulating agent.Preferably the viscosity modulating agent is a gelling or thickeningagent. The viscosity modulating agent may be a thickening agent andsuitable thickening agents include polyvinyl pyrrolidone. In someembodiments, the thickening agent is an antiperspirant or thecomposition further includes an antiperspirant and/or a deodorant.

In this specification and the claims, the term “viscosity modulatingagent” is used to refer to a component of the composition which altersthe viscosity of the overall resulting composition. The nature of theviscosity modulating agent depends not only on the agent itself, butalso the proportion in which it is present and the presence or absenceof other components. For example, a gelling agent may act as a viscositymodulating agent providing that an activator for that gelling agent ispresent. For example, hydroxypropylmethylcellulose (HPMC) may be used ina composition with an activator, in which the volatile solvent is alower alkyl alcohol at a concentration of around 2% w/w. A suitableactivator would be sodium chloride. Concentration may be important as,in this example, at 0.1% w/w HPMC has different effects. A thickeningagent is one which increases viscosity, and is often anhydrous.Viscosity modulating agents are further described below.

Further, the term “transdermal” is used co-terminously with “topical” indescribing the application of agents to the skin. Both terms “topical”and “transdermal” are used herein in the broadest sense to refer toadministration of a drug to the skin surface of an animal, includinghumans, so that the drug passes through the skin tissue. Unlessotherwise stated or implied, the terms topical drug delivery andtransdermal drug delivery are used interchangeably. From a strictdrug-delivery perspective, “transdermal” is sometimes used to refer onlyto systemic delivery through the skin whereas “topical” requires onlydelivery into or on the skin for local effect. The invention describedin this specification is equally applicable to both transdermal andtopical modes of delivery, and is described here as “transdermal” onlyfor convenience. For avoidance of doubt, the invention provides invarious embodiments compositions and methods suitable for topicalapplication corresponding to those described in the specification astransdermal applications.

Typically, the composition appears like a lotion. In this context,“lotion” is used in its broad descriptive sense, rather than the morespecific formulatory sense which refers to a mixed phase or suspensionof active. The composition of the invention is often a true solution,but with increased viscosity so that its viscosity is more similar tothat usually associated with a lotion. The viscosity of the compositionis preferably greater than that of water but less than about 300centipoise. The viscosity in different embodiments is in the range of 10to 200, 20 to 100 or 30 to 50 centipoise.

In another embodiment, there is provided a transdermal drug deliverycomposition which includes at least one physiologically active, at leastone volatile solvent, and at least one viscosity modulating agent andwithout a penetration enhancer.

In a different embodiment, there is provided a transdermal drug deliverycomposition which includes at least one physiologically active agent, atleast one volatile solvent, at least one viscosity modulating agent, andat least one penetration enhancer. The penetration enhancer assists inthe uptake of the physiologically active agent at least through theouter layers of the skin, typically to form a reservoir of active withinthe skin. Typical penetration enhancers suitable for use in theinvention are further described below.

The volatile solvent (also sometimes called a “volatile carrier” or“vehicle”) will typically be present in a higher concentration, such as80% or more w/w. The volatile solvent may be any such solvent that ispharmacologically suitable and many such solvents are known in the art.One of the advantages of the inclusion of a volatile solvent or volatilecarrier is that it facilitates the composition to dry rapidly, allow theabsorption of the active agent, and avoid the problems of accidentallydosing others by confining administration to a small area of skin,preferably the axilla. Preferably the volatile solvent has a vapourpressure above 35 mm Hg at atmospheric pressure and normal skintemperature of 32 degrees Celsius.

Preferably, the solvent is a lower alkyl alcohol or a mixture of suchalcohols. Suitable solvents include ethanol, ethyl acetate, isopropanol,acetone, ethyl formate, methyl acetate, methyl ethyl ketone, pentane andchloroform or mixture thereof in the range of about 40 to 99% v/v of thecomposition, preferably more than 50%, 60%, 70% or 80%. An aerosolpropellant, such as dimethyl ether or R134a, may also constitute avolatile solvent for the purpose of the present invention.

Preferably the compositions of the invention are non-occlusive, in thatin the broadest sense, the composition is not trapped to the skin, orthe skin is not closed to the atmosphere, by means of a patch device,fixed reservoir, application chamber, tape, bandage, sticking plaster,or the like, which remains on the skin a the site of application for aprolonged length of term. Such devices tend to be uncomfortable for thewearer or can be embarrassing or unsightly.

The viscosity modulating agent will commonly be a thickening agent or agelling agent. It will often be used to increase the viscosity of thecomposition containing a solution of the physiologically active agent inthe volatile solvent. Given the nature of the volatile solvents, thesolution will typically have very low viscosity. The purpose of theviscosity modulating agent is to increase the viscosity of the solutionsuch that the composition is retained in the vicinity of the area ofapplication for a brief period of time so as to permit increased uptakeof the physiologically active agent at that site. The viscositymodulating agent will typically increase the viscosity to about that ofa typical lotion (eg, sunscreen), but not to the point where thecomposition becomes a gel. Typically, the viscosity of a transdermaldrug delivery composition according to the invention will be less than300 centipoise and often about 150 centipoise.

The viscosity modulating agent must retain its activity in the contextof the other components of the composition of the invention. Inparticular, the thickening agent must remain active and stable in thisenvironment. For example, where the composition has a high alcoholcontent (for example, where the volatile solvent comprises primarilyalcohol at greater than 80% v/v), the thickening agent must be effectivein a high alcoholic environment. Having these requirements in mind, askilled person can select several thickening agents from those known inthe art. Desirably, a thickening agent also inhibits the solventevaporation rate so as to enhance the so-called “solvent burst” ofactive agent into the skin at the site of application.

It will be appreciated by one skilled in the art that the amount ofthickening agent required is a question of degree and compromise withother parameters. It is also known that many thickening agents have peakactivity at a particular concentration, and that activity may drop offsubstantially with slightly higher and slightly lower percentageconcentrations. For example, in one preferred embodiment where thecomposition comprises over 80% alcohol and the thickening agent used isPVP, the desirable concentration of PVP is between 1 and 3%, and itsactivity is substantially reduced outside that range.

Gelling agents are matrix-forming agents which, once activated, act byforming a matrix within and around the composition they are in.Thickening agents are usually anhydrous agents which increase theviscosity of the composition. In one embodiment, a thickening agent isused. The thickening agent may be an antiperspirant and/or an occlusiveagent for the drug delivery composition. In another embodiment, both adeodorant and an antiperspirant are in a composition with the at leastone active agent and dermal penetration enhancer. Suitable thickeningagents include polyvinyl pyrrolidone or PVP (Povidone™). Theantiperspirant may be an occlusive agent also, and a thickening,occlusive agent may have antiperspirant effects.

Despite the inherent antiperspirant and/or deodorant properties of thecompositions of the invention, the composition may be optionallyadministered with deodorant and antiperspirant additives that do notinterfere with the active. In another form, there is provided atransdermal drug delivery composition which includes at least onephysiologically active agent; and at least one volatile solvent; and atleast one antiperspirant or deodorant.

The antiperspirant agent may be any suitable substance that reduces orinhibits the production of perspiration. In some instances, anantiperspirant agent can also provide deodorant benefits. Preferably,the antiperspirant agent is selected from the group consisting ofinorganic or organic salts of aluminium, zirconium, zinc or mixturesthereof.

In one embodiment, the antiperspirant agent is an aluminium salt havingthe general formula:Al₂(OH)_(x)Q_(y) .wH₂O

-   -   where Q is chlorine, bromine or iodine;    -   x is 2 to 5;    -   x+y=6, where x and y do not need to be integers; and    -   wH₂O represents a variable amount of hydration.

In another embodiment, the antiperspirant agent is a zirconium salt ofthe following general formula:ZrO(OH)_(2n-nz)B_(z) .wH₂Owhere

-   -   z is a variable in the range of from 0.9 to 2.0 so that the        value of 2n−nz is zero or a positive;    -   n is the valency of B;    -   B is selected from the group consisting of chloride, other        halide, sulphamate, sulphate and mixtures thereof; and    -   wH₂O represents a variable amount of hydration.

In a preferred embodiment, the antiperspirant agent is selected from thegroup consisting of aluminium chloride, aluminium chlorohydrate,aluminium chlorohydrex polyethylene glycol, aluminium chlorohydrexpropylene glycol, aluminium dichlorohydrate, aluminium dichlorohydrexpolyethylene glycol, aluminium dichlorohydrex propylene glycol,aluminium sesquichlorohydrate, aluminium sesquichlorohydrex polyethyleneglycol, aluminium sesquichlorohydrex propylene glycol, aluminiumzirconium octachlorohydrate, aluminium zirconium octachlorohydrex gly,aluminium zirconium pentachlorohydrate, aluminium zirconiumpentachlorohydrex gly, aluminium zirconium tetrachlorohydrate, aluminiumzirconium tetrachlorohydrex gly, aluminium zirconium trichlorohydrateand aluminium zirconium trichlorohydrex gly. These antiperspirant agentshave approved listings under the United States Food & DrugAdministration Federal Register.

The present invention also contemplates that other antiperspirant agentsmay also be used. Examples of these antiperspirant agents includealuminium bromohydrate, aluminium chloride, aluminium citrate, aluminiumsulfate, ammonium alum, cobalt acetylmethionate, potassium alum, sodiumalum and sodium aluminium chlorohydroxy lactate.

In another embodiment, the composition of the invention comprises adeodorant agent. The deodorant agent may be any suitable substance thatprovides deodorancy benefits in masking or neutralising odours that areproduced by the action of bacteria. Generally, deodorant agents do notinterfere with the production of perspiration. Representative examplesof deodorant agents include, but are not limited to, one or more ofcetyl-trimethylammonium bromide, cetyl pyridinium chloride, benzethoniumchloride, diisobutyl phenoxy ethoxy ethyl dimethyl benzyl ammoniumchloride, sodium N-lauryl sarcosine, sodium N-palmithyl sarcosine,lauroyl satcosine, N-myristoyl glycine, potassium N-lauryl sarcosine,stearyl, trimethyl ammonium chloride, sodium aluminium chlorohydroxylactate, tricetylmethyl ammonium chloride, 2,4,4′-trichloro-2′-hydroxydiphenyl ether, diaminoalkyl amides such as L-lysine hexadecyl amide,heavy metal salts of citrate, salicylate, and piroctose, especially zincsalts, and acids thereof, heavy metal salts of pyrithione, especiallyzinc pyrithione and zinc phenolsulfate. Other deodorant agents include,without limitation, odour absorbing materials such as carbonate andbicarbonate salts, e.g. as the alkali metal carbonates and bicarbonates,ammonium and tetraalkylammonium carbonates and bicarbonates, especiallythe sodium and potassium salts, or any combination of the above.

In a preferred embodiment, the composition comprises a combination ofantiperspirant and deodorant agents.

The antiperspirant and deodorant agents may be present in thecomposition in any amount that provides beneficial antiperspirant and/ordeodorancy effects. The antiperspirant agent or deodorant agent may bepresent in an amount of from about 0.05 to 60%, and is preferably fromabout 1 to 40%, more preferably from about 5 to 30% and even morepreferably from about 8 to 15% by weight of the composition. Where thecomposition of the invention comprises a combination of antiperspirantand deodorant agents, the combined amounts of these agents is preferablywithin the preferred range stated above.

The composition may be applied to any area of skin. Preferably it isapplied to areas of skin having increased cutaneous blood flow, such asthe axilla, scrotum, between toes, groin, plantar arch of the foot orpalm of the hand. Other suitable areas include where there is suitablypermeable skin. In particularly, it is desirable to apply it to only oneor more of these areas while still effectively delivering the requireddose of active agent. It is also known that some areas of the skin arerelatively more permeable to active agents than others. The invention isusefully employed to deliver active agent through these areas only, thuslimiting the total area of skin to which the composition must be appliedin order to deliver an effective dose of the active agent.

Moreover, the invention provides a method for transdermal delivery of anactive agent to areas of the skin prone to perspiration, particularlyhigher rates of perspiration relative to other areas. Such areas of skinhave typically not been preferred for transdermal delivery because ofthe desirability for patients to be able to maintain use ofantiperspirants and deodorants. In a preferred form, the method providesfor administration of a composition including the active agent to thoseareas of skin which provide maximal systemic absorption. It is believedthat this is due, at least in part, to increased cutaneous blood flowand heat. These areas may be one of more of the axilla, scrotum, groin,planter arch of foot, palm of hand or forehead. Preferably the area isat least one axilla. These areas in particular may benefit greatly fromthe antiperspirant and/or deodorant effects of the composition when itis applied.

In another form, the invention comprises a method of delivering anactive agent systemically to a patient by application of the activeagent to one or more axilla. The active agent is preferably in atransdermal drug delivery composition as described in thisspecification. Preferably, administration is essentially only to theaxilla. In another form, administration is to areas selected from thegroup consisting of the axilla, scrotum, groin, planter arch of foot,palm of hand and forehead. In one form, the method avoids application oradministration of the composition to the upper arms, shoulders orabdomen of a subject. The transdermal drug delivery composition of thepresent invention is capable, upon application to an area of skin, ofdelivering a therapeutically effective amount of active agent to thesystemic circulation.

The composition may be applied to any area of skin on a subject,selected from one or more of planter foot arch, lateral ankle, palm,upper arm, ventral forearm, dorsal forearm, back, chest, thigh, abdomen,groin, scalp, axilla, forehead, lower back, buttocks or scrotum. Thecomposition is preferably applied to those areas of skin which providemaximal systemic absorption due to increased cutaneous blood flow andheat. These areas may be one of more of the axilla, scrotum, planterarch of foot, palm of hand or forehead. Preferably the area is at leastone axilla. These areas in particular may benefit greatly from theantiperspirant and/or deodorant effects of the composition when it isapplied.

A further advantage of the compositions according to the invention isthat a therapeutically effective amount may be applied to a minimalsurface area, therefore minimising the unpleasant side effects andpatient inconvenience associated with applying large amounts of acomposition to a large surface area. Preferably the area of skin towhich the composition is applied is less than 500 cm². Desirably, thearea is less than 300 cm², 100 cm², 50 cm², 20 cm² 10 cm², and 5 cm².

A key advantage achievable with some embodiments of the invention isincreased flux of the active, thereby enabling a greater proportion ofactive in a dose to be delivered to the patient and utilising a smallerarea of skin. In some cases, a much smaller area than used to date isrequired, consequently improving patient acceptability and compliance.This is particularly applicable where the active otherwise has poor orlow flux, a large systemic dose is desired and/or a faster onset ofaction is desired.

The penetration enhancer is also sometimes called an “absorption”enhancer. A number of penetration enhancers may be utilised includingfatty acids, fatty acid esters, fatty alcohols, glycols and glycolesters, 1,3-dioxolanes and 1,3-dioxanes, macrocyclic ketones containingat least 12 carbon atoms, oxazolidinones and oxazolidinone derivatives,alkyl-2-(N,N-disubstituted amino)-alkanoate esters, (N,N-disubstitutedamino)-alkanol alkanoates, sunscreen esters and mixtures thereof. Mostpreferably the dermal penetration enhancer is selected from the listincluding oleic acid, oleyl alcohol, cyclopentadecanone (CPE-218™),sorbitan monooleate, glycerol monooleate, propylene glycol monolaurate,polyethylene glycol monolaurate, 2-n-nonyl 1,3-dioxolane (SEPA™),dodecyl 2-(N,N-dimethylamino)-propionate (DDAIP) or its saltderivatives, 2-ethylhexyl 2-ethylhexanoate, isopropyl myristate,dimethyl isosorbide, 4-decyloxazolidinon-2-one (SR-38™, TCPI, Inc.),3-methyl-4-decyloxazolidinon-2-one, octyl dimethyl-para-aminobenzoate,octyl para-methoxycinnamate, octisalate and mixtures thereof.

Preferred penetration enhancers are sunscreen esters such as thecompounds disclosed in our U.S. Pat. No. 6,299,900 the contents of whichare herein incorporated by reference. These include the compounds beingsafe skin-tolerant ester sunscreens of formula:

-   -   wherein R¹ is hydrogen, lower alkyl, lower alkoxy, halide,        hydroxy or NR³R⁴;    -   R² is long chain alkyl;    -   R³ and R⁴ are each independently hydrogen, lower alkyl or R³ and        R⁴ together with the nitrogen atom to which they are attached        form a 5- or 6-membered heterocyclic ring;    -   n is 0 or 1; and    -   q is 1 or 2.

Preferred penetration enhancers are esters having a long chain alkylpara-aminobenzoate, long chain alkyl dimethyl-para-aminobenzoate, longchain alkyl cinnamate, long chain alkyl methoxycinnamate or long chainalkyl salicylate; most preferably the penetration enhancer is one or amixture of octyl dimethyl-para-aminobenzoate (“Padimate O”), octylpara-methoxycinnamate and octyl salicylate (“octisalate” per USP).

The concentration of absorption/penetration enhancer may be in the rangefrom 10-10,000 weight percent of absorption/penetration enhancer basedupon the weight of active ingredient. The ratio of penetration enhancerto active ingredient may vary considerably and will be governed as muchas anything, by the pharmacological results that are required to beachieved. In principle, it is desirable that as little absorptionenhancer as possible is used. However, usually the penetration enhanceris in the range from 0.01-15% of the total composition.

Heat can also act to enhance penetration of an active agent, togetherwith or independently of such a penetration enhancer. Heat is not itselfregarded as a “penetration enhancer”. Without being bound by the theoryor mode of action, it is believed that heat can disrupt and/or fluidisethe lipid structures in the skin to enhance penetration. Accordingly, inone embodiment, the invention provides at least one physiologicallyactive agent and at least one viscosity modulating agent which isapplied in the presence of heat. Preferably, the composition alsoincludes a dermal penetration enhancer.

Heat may result from utilising the patient's own body heat to warm theskin to the core body temperature (the outer layers of skin often beingbelow that temperature) and/or the heat may be from an external source.Such external sources include conventional heat packs (eg, fortherapeutic or physiotherapeutic uses), radiation heat (eg, heat lamps),exothermic chemical reactions or in situ generation of heat.

Heat is suggested to enhance the transdermal delivery of various drugsby increasing skin permeability, body fluid circulation, blood vesselwall permeability, rate-limiting membrane permeability, and drugsolubility. Accordingly, whether or not heat is applied around the timeof application of the composition, application of a transdermalcomposition is preferably to areas of skin having increased cutaneousblood flow, and therefore warmer. Such areas include but are not limitedto, the planter arch of the foot, palm of the hand, axilla and scrotum.However associated with areas of increased heat is increasedperspiration and perspiration related body odour. Therefore, it isdesirable if the transdermal composition is also an antiperspirantand/or a deodorant. An antiperspirant reduces the amount of perspirationproduced by blocking the sweat glands. A deodorant masks or covers theodour associated with perspiration, using either fragrance or ananti-bacterial ingredient to reduce odour-causing bacteria on the skin.Antiperspirants can have an indirect deodorant effect in the underarmarea, but a deodorant cannot act as an antiperspirant. It is furtherdesirable if known antiperspirants and/or deodorants can be added to thecomposition without inhibiting drug delivery.

Without being bound by any theory, the applicant believes that theviscosity modulating agent and/or penetration enhancer in thecomposition function to minimise perspiration, and that the volatilecarrier functions to inhibit bacteria and therefore odour by abactericidal activity of the carrier.

In one embodiment, the composition consists essentially of onephysiologically active agent; one volatile solvent; and one viscositymodulating agent, each as described above. Preferably, it furtherincludes a penetration enhancer as described above. In one embodiment,the viscosity modulating agent is an antiperspirant, and the compositionoptionally also includes a deodorant. Each of these embodiments may ormay not also include water.

The invention also provides a use of at least one physiologically activeagent; and at least one volatile solvent; and at least one viscositymodulating agent in the manufacture of a medicament for transdermaldelivery of the active agent to a subject. The medicament is preferablyfor treatment or prevention of a condition treatable or preventable bythe active.

In another embodiment of the invention, the composition may include atleast one additional active agent and/or at least one additionalinactive agent. In a different embodiment, the composition does notinclude a herbal extract (or like component), whether as aphysiologically active agent or otherwise.

The transdermal drug delivery composition of the present invention iscapable, upon application to an area of skin, of delivering atherapeutically effective amount of active agent to the systemiccirculation. Accordingly, in one aspect, there is provided a method oftransdermal delivery of an active agent comprising applying to an areaof skin of a subject the transdermal composition described above. Inparticular, the method can be used to deliver a predetermined amount ofactive and/or sufficient active to achieve a predetermined bloodstreamlevel or concentration of the active. For some actives (eg, those with ashort half-life) other measures of the amount of active delivered willbe appropriate.

The composition may also be administered by other known topicaltechniques including a lotion, gel, spray etc. These can be formulatedby adding suitable carriers, excipients and thixotropic agents which areinert to the active to facilitate retaining the composition on the skinsufficiently for delivery of the active agent as contemplated by theinvention.

The transdermal composition of the invention and the composition used inthe method of the invention may be applied, including but not limited toaxilla, of a subject in any of a range of forms. Suitable forms includefor example lotions, gels, foams, pastes, soft solids, firm sticks,solutions, sprays, aerosols, roll-ons and the like, each of whichrepresent different forms of the invention. The composition may beapplied in an occlusive or non-occlusive manner. It is preferred thatthe composition is applied in a non-occlusive manner and in the mostpreferred embodiment the composition is applied as a lotion, aerosol orspray.

The transdermal composition of the invention and the composition used inthe method of the invention may further comprise additional componentsthat will facilitate its preparation into forms suitable for applicationto the axilla of a subject. Examples of additional components includebut are not limited to surfactants, buffers, solvents and propellants.

It is particularly preferred that the composition of the invention andthe composition used in the method of the invention is applied withoutbeing covered by adhesives, adhered patches, adhered bandages or films.Such devices tend to be uncomfortable for the wearer or can beembarrassing or unsightly. The invention allows non-occlusiveadministration of physiologically active agents by the transdermalcompositions in the axilla under the subjects clothing.

In applying the composition of the invention, an antiperspirant and/or adeodorant may be applied at about the same time as the composition.Preferably, the antiperspirant and/or deodorant is applied afterapplication of the composition of the invention. As noted above, in someembodiments of the invention, an antiperspirant and/or a deodorant maybe incorporated within the composition, thus requiring only onesubstance to be applied by a patient. The antiperspirant and/ordeodorant will be selected from those which do not interfere with thedrug delivery mechanism. Preferably, the antiperspirant and deodorantadded complement the natural antiperspirant and deodorising propertiesof the transdermal drug delivery composition itself as described above.

The invention also provides a method of transdermal drug deliverycomprising applying a predetermined dose of a transdermal drug deliverycomposition as described above to a patient. As described below, apreferred form of the invention involves applying the composition to atleast one axilla. In the composition of the invention, the inventionextends to a method in which an antiperspirant and/or a deodorant isapplied to the axilla region at about the same time as the transdermaldrug delivery composition is applied. Preferably, the antiperspirantand/or deodorant is applied after the transdermal drug deliverycomposition is applied to at least one axilla region.

In the methods of the invention the compositions are preferablyadministered without being covered by an adhesive bandage, patch orother physical barrier bonded to the administration area. Preferably thetransdermal composition becomes touch dry within three minutes ofapplication to the area of skin, more preferably within about oneminute.

The antiperspirant and/or deodorant properties of the composition areparticularly advantageous when the physiologically active agent istestosterone or derivatives thereof for treating testosterone deficiencyin a subject. Testosterone is responsible for increasing perspirationand producing perspiration and perspiration related odour in thepresence of 5-alpha-reductase, due to the conversion of testosterone todihydrotestosterone (DHT). Accordingly there is provided a compositionas described above in which the physiologically active agent is selectedfrom at least one or more of androgenic compound, such as testosteroneor derivatives thereof. The physiologically active agent may thereforebe selected from androgenic compounds which are syntheticallyderivatized from testosterone and are known to provide the same or asimilar physiological activity. Such compounds include withoutlimitation, testosterone salts, such as acetate, enanthate, cypionate,isobutyrate, dehydro-epiandrosterone, propionate, undecanoate esters andcyproterone acetate. In other embodiments, one or more of the followingare included: 5-alpha-reductase inhibitors (such as finasteride,turosteride, LY-191704 and MK-386). Other suitable compounds includemethyltestosterone, clostebol acetate, drostanolone, furazabol,nandrolone oxandrolone, stanozolol, trenbolone acetate,dihydro-testosterone, 17-.alpha.-methyl-19-nortestosterone andfluoxymesterone.

Contrary to what might be expected from the activity of testosterone,the applicant has found that testosterone may be administered inaccordance with the invention to provide rapid delivery without inducingsweating and odour that distress a subject. The unacceptable levels ofthese side effects identified in the art have been attributed to thepresence of elevated testosterone.

In a preferred embodiment of this aspect of the invention, the inventionprovides a method of treatment of testosterone deficiency in a subjectcomprising topically applying to an area of skin of a subject atransdermal composition comprising:

-   -   a physiologically active agent selected from at least one of        testosterone or derivatives thereof;    -   a volatile carrier;    -   at least one dermal penetration enhancer; and    -   at least one viscosity modulating agent.

In one embodiment, the carrier is isopropyl alcohol, the penetrationenhancer is octisalate, the active agent is testosterone and thethickening agent is polyvinylpyrrolidone. These may be in the followingpercentages:

-   -   30% v/v carrier;    -   8% w/v enhancer;    -   1% w/v active;    -   2% w/v thickener;    -   10% v/v sterile water; and    -   the balance ethanol.

In another embodiment, there is provided a transdermal drug deliverycomposition consisting essentially of the above 6 components in thoseproportions. In another form of the invention, these 6 components inthese proportions are used in the manufacture of a medicament for thetreatment of a subject, particular a subject in need of treatment withthe active. For example, a subject suffering from decreased testosteroneblood levels is treated with a composition where the active istestosterone or a related androgenic agent or testosterone derivative asset out above.

In further embodiments, the invention provides a method of treatment ofoestrogen and/or progestin deficiency, a method of treatment of chronicpain, and a method of treatment of anxiety related disorders. Otheractives as set-out below are also contemplated for use with theinvention.

In one embodiment, a composition containing testosterone as the activeagent is applied to the axilla of a patient to deliver testosteroneresulting in a blood level of at least a predetermined amount. In oneembodiment, the predetermined amount is the normal range. In the case oftestosterone, the blood level achieved is at least 200 ng/dL, preferably300-1000 ng/dL. Preferably, the composition is only applied to theaxilla.

Physiologically active agents that may be used in the transdermal drugdelivery compositions of the present invention include any locally orsystemically active agents which are compatible with the penetrationenhancers of the present invention and which can be delivered throughthe skin, particularly with the assistance of the dermal penetrationenhancer to achieve a desired effect. These active agents are preferablytherapeutics, and include (grouped by therapeutic class):

-   (a) Alimentary System agents including antidiarrhoeals such as    diphenoxylate, loperamide and hyoscyamine.-   (b) Cardiovascular System agents including:    -   (i) antihypertensives such as hydralazine, minoxidil, captopril,        enalapril, clonidine, prazosin, debrisoquine, diazoxide,        guanethidine, methyldopa, reserpine, trimetaphan;    -   (ii) Calcium channel blockers such as diltiazem, felodopine,        amlodipine, nitrendipine, nifedipine and verapamil;    -   (iii) antiarrhythmics such as amiodarone, flecainide,        disopyramide, procainamide, mexiletene and quinidine;    -   (iv) antiangina agents such as glyceryl trinitrate, erythritol        tetranitrate, pentaerythritol tetranitrate, mannitol        hexanitrate, perhexilene, isosorbide dinitrate and nicorandil;    -   (v) beta-adrenergic blocking agents such as alprenolol,        atenolol, bupranolol, carteolol, labetalol, metoprolol, nadolol,        nadoxolol, oxprenolol, pindolol, propranolol, sotalol, timolol        and timolol maleate;    -   (vi) cardiotonic glycosides such as digoxin and other cardiac        glycosides and theophylline derivatives;    -   (vii) adrenergic stimulants such as adrenaline, ephedrine,        fenoterol, isoprenaline, orciprenaline, rimeterol, salbutamol,        salmeterol, terbutaline, dobutamine, phenylephrine,        phenylpropanolamine, pseudoephedrine and dopamine;    -   (viii) vasodilators such as cyclandelate, isoxsuprine,        papaverine, dipyrimadole, isosorbide dinitrate, phentolamine,        nicotinyl alcohol, co-dergocrine, nicotinic acid, glyceryl        trinitrate, pentaerythritol tetranitrate and xanthinol; and    -   (ix) antimigraine preparations such as ergotamine,        dihydroergotamine, methysergide, pizotifen and sumatriptan.-   (c) Drugs Affecting Blood and Haemopoietic Tissues including:    -   (i) Anticoagulants and thrombolytic agents such as warfarin,        dicoumarol, low molecular weight heparins such as enoxaparin;        streptokinase and its active derivatives; and    -   (ii) haemostatic agents such as aprotinin, tranexamic acid and        protamine.-   (d) Drugs Affecting the Central Nervous System including:    -   (i) Analgesics;    -   (ii) antipyretics including the opioid analgesics such as        buprenorphine, dextromoramide, dextropropoxyphene, fentanyl,        alfentanil, sufentanil, hydromorphone, methadone, morphine,        oxycodone, papaveretum, pentazocine, pethidine, phenoperidine,        codeine and dihydrocodeine; and    -   (iii) Others include acetylsalicylic acid (aspirin),        paracetamol, and phenazone.-   (e) Hypnotics and sedatives such as the barbiturates,    amylobarbitone, butobarbitone and pentobarbitone and other hypnotics    and sedatives such as choral hydrate, chlormethiazole, hydroxyzine    and meprobamate.-   (f) Antianxiety agents such as the benzodiazepines, alprazolam,    bromazepam, chlordiazepoxide, clobazam, chlorazepate, diazepam,    flunitrazepam, flurazepam, lorazepam, nitrazepam, oxazepam,    temazepam and triazolam.-   (g) Neuroleptic and antipsychotic drugs such as the phenothiazines,    chlorpromazine, fluphenazine, pericyazine, perphenazine, promazine,    thiopropazate, thioridazine and trifluoperazine and the    butyrophenones, droperidol and haloperidol and the other    antipsychotic drugs such as pimozide, thiothixene and lithium.-   (h) Antidepressants such as the tricyclic antidepressants    amitryptyline, clomipramine, desipramine, dothiepin, doxepin,    imipramine, nortriptyline, opipramol, protriptyline and trimipramine    and the tetracyclic antidepressants such as mianserin and the    monoamine oxidase inhibitors such as isocarboxazid, phenelizine,    tranylcypromine and moclobemide and selective serotonin re-uptake    inhibitors such as fluoxetine, paroxetine, citalopram, fluvoxamine    and sertraline.-   (i) CNS stimulants such as caffeine.-   (j) Anti-alzheimer's agents such as tacrine.-   (k) Anti-parkinson agents such as amantadine, benserazide,    carbidopa, levodopa, benztropine, biperiden, benzhexol, procyclidine    and dopamine-2 agonists such as    S(−)-2-(N-propyl-N-2-thienylethylamino)-5-hydroxytetralin (N-0923).-   (l) Anticonvulsants such as phenytoin, valproic acid, primidone,    phenobarbitone, methylphenobarbitone and carbamazepine,    ethosuximide, methsuximide, phensuximide, sulthiame and clonazepam.-   (m) Antiemetics, antinauseants such as the phenothiazines,    prochloperazine, thiethylperazine and 5HT-3 receptor antagonists    such as ondansetron and granisetron and others such as    dimenhydrinate, diphenhydramine, metoclopramide, domperidone,    hyoscine, hyoscine hydrobromide, hyoscine hydrochloride, clebopride    and brompride.-   (n) Musculoskeletal System including:    -   (i) Non-steroidal anti-inflammatory agents including their        racemic mixtures or individual enantiomers where applicable,        such as ibuprofen, flurbiprofen, ketoprofen, aclofenac,        diclofenac, aloxiprin, aproxen, aspirin, diflunisal, fenoprofen,        indomethacin, mefenamic acid, naproxen, phenylbutazone,        piroxicam, salicylamide, salicylic acid, sulindac,        desoxysulindac, tenoxicam, tramadol and ketoralac;    -   (ii) Additional non-steroidal antiinflammatory agents which can        be formulated in combination with the dermal penetration        enhancers include salicylamide, salicylic acid, flufenisal,        salsalate, triethanolamine salicylate, aminopyrine, antipyrine,        oxyphenbutazone, apazone, cintazone, flufenamic acid,        clonixeril, clonixin, meclofenamic acid, flunixin, coichicine,        demecolcine, allopurinol, oxypurinol, benzydamine hydrochloride,        dimefadane, indoxole, intrazole, mimbane hydrochloride,        paranylene hydrochloride, tetrydamine, benzindopyrine        hydrochloride, fluprofen, ibufenac, naproxol, fenbufen,        cinchophen, diflumidone sodium, fenamole, flutiazin, metazamide,        letimide hydrochloride, nexeridine hydrochloride, octazamide,        molinazole, neocinchophen, nimazole, proxazole citrate, tesicam,        tesimide, tolmetin, and triflumidate;    -   (iii) Antirheumatoid agents such as penicillamine,        aurothioglucose, sodium aurothiomalate, methotrexate and        auranofin;    -   (iv) Muscle relaxants such as baclofen, diazepam,        cyclobenzaprine hydrochloride, dantrolene, methocarbamol,        orphenadrine and quinine; and    -   (v) Agents used in gout and hyperuricaemia such as allopurinol,        colchicine, probenecid and sulphinpyrazone.-   (o) Hormones and Steroids including:    -   (i) Oestrogens such as oestradiol, oestriol, oestrone,        ethinyloestradiol, mestranol, stilboestrol, dienoestrol,        epioestriol, estropipate and zeranol;    -   (ii) Progesterone and other progestagens such as allyloestrenol,        dydrgesterone, lynoestrenol, norgestrel, norethyndrel,        eclometrine, norethisterone, norethisterone acetate, gestodene,        levonorgestrel, medroxyprogesterone and megestrol;    -   (iii) Antiandrogens such as cyproterone acetate and danazol;    -   (iv) Antioestrogens such as tamoxifen and epitiostanol and the        aromatase inhibitors, exemestane and 4-hydroxy-androstenedione        and its derivatives. Androgens and anabolic agents such as        testosterone, methyltestosterone, clostebol acetate,        drostanolone, furazabol, nandrolone oxandrolone, stanozolol,        trenbolone acetate, dihydro-testosterone,        17-.alpha.-methyl-19-nortestosterone and fluoxymesterone;    -   (v) 5-alpha reductase inhibitors such as finasteride,        turosteride, LY-191704 and MK-386;    -   (vi) Corticosteroids such as betamethasone, betamethasone        valerate, cortisone, dexamethasone, dexamethasone 21-phosphate,        fludrocortisone, flumethasone, fluocinonide, fluocinonide        desonide, fluocinolone, fluocinolone acetonide, fluocortolone,        halcinonide, halopredone, hydrocortisone, hydrocortisone        17-valerate, hydrocortisone 17-butyrate, hydrocortisone        21-acetate methylprednisolone, prednisolone, prednisolone        21-phosphate, prednisone, triamcinolone, triamcinolone        acetonide;    -   (vii) Further steroidal antiinflammatory agents such as        cortodoxone, fluoracetonide, fludrocortisone, difluorsone        diacetate, flurandrenolone acetonide, medrysone, amcinafel,        amcinafide, betamethasone and its other esters,        chloroprednisone, clorcortelone, descinolone, desonide,        dichlorisone, difluprednate, flucloronide, flumethasone,        flunisolide, flucortolone, fluoromethalone, fluperolone,        fluprednisolone, meprednisone, methylmeprednisolone,        paramethasone, cortisone acetate, hydrocortisone        cyclopentylpropionate, cortodoxone, flucetonide, fludrocortisone        acetate, flurandrenolone acetonide, medrysone, amcinafal,        amcinafide, betamethasone, betamethasone benzoate,        chloroprednisone acetate, clocortolone acetate, descinolone        acetonide, desoximetasone, dichlorisone acetate, difluprednate,        flucloronide, flumethasone pivalate, flunisolide acetate,        fluperolone acetate, fluprednisolone valerate, paramethasone        acetate, prednisolamate, prednival, triamcinolone hexacetonide,        cortivazol, formocortal and nivazol;    -   (viii) Pituitary hormones and their active derivatives or        analogs such as corticotrophin, thyrotropin, follicle        stimulating hormone (FSH), luteinising hormone (LH) and        gonadotrophin releasing hormone (GnRH);    -   (ix) Thyroid hormones such as calcitonin, thyroxine and        liothyronine and antithyroid agents such as carbimazole and        propylthiouracil; and    -   (x) Other miscellaneous hormone agents such as octreotide.-   (q) Pituitary inhibitors such as bromocriptine.-   (r) Ovulation inducers such as clomiphene.-   (s) Hypoglycaemic agents such as insulin, chlorpropamide,    glibenclamide, gliclazide, glipizide, tolazamide, tolbutamide,    rosiglitazone and mefformin.-   (t) Genitourinary System agents.-   (u) Diuretics such as the thiazides, related diuretics and loop    diuretics, bendrofluazide, chlorothiazide, chlorthalidone, dopamine,    cyclopenthiazide, hydrochlorothiazide, indapamide, mefruside,    methycholthiazide, metolazone, quinethazone, bumetanide, ethacrynic    acid and frusemide and potassium sparing diuretics, spironolactone,    amiloride and triamterene.-   (v) Antidiuretics such as desmopressin, lypressin and vasopressin    including their active derivatives or analogs.-   (w) Obstetric drugs including agents acting on the uterus such as    ergometrine, oxytocin and gemeprost.-   (x) Prostaglandins such as alprostadil (PGE1), prostacyclin (PGI2),    dinoprost (prostaglandin F2-alpha) and misoprostol.-   (y) Antimicrobials including:    -   (i) cephalosporins such as cephalexin, cefoxytin and        cephalothin;    -   (ii) penicillins such as amoxycillin, amoxycillin with        clavulanic acid, ampicillin, bacampicillin, benzathine        penicillin, benzylpenicillin, carbenicillin, cloxacillin,        methicillin, phenethicillin, phenoxymethylpenicillin,        flucloxacillin, mezlocillin, piperacillin, ticarcillin and        azlocillin;    -   (iii) tetracyclines such as minocycline, chlortetracycline,        tetracycline, demeclocycline, doxycycline, methacycline and        oxytetracycline and other tetracycline-type antibiotics;    -   (iv) minoglycosides such as amikacin, gentamicin, kanamycin,        neomycin, netilmicin and tobramycin. Antifungals such as        amorolfine, isoconazole, clotrimazole, econazole, miconazole,        nystatin, terbinafine, bifonazole, amphotericin, griseofulvin,        ketoconazole, fluconazole and flucytosine, salicylic acid,        fezatione, ticlatone, tolnaftate, triacetin, zinc, pyrithione        and sodium pyrithione;    -   (v) Quinolones such as nalidixic acid, cinoxacin, ciprofloxacin,        enoxacin and norfloxacin. Sulphonamides such as        phthalylsulphthiazole, sulfadoxine, sulphadiazine,        sulphamethizole and sulphamethoxazole;    -   (vi) Sulphones such as dapsone; and    -   (vii) Other miscellaneous antibiotics such as chloramphenicol,        clindamycin, erythromycin, erythromycin ethyl carbonate,        erythromycin estolate, erythromycin glucepate, erythromycin        ethylsuccinate, erythromycin lactobionate, roxithromycin,        lincomycin, natamycin, nitrofurantoin, spectinomycin,        vancomycin, aztreonam, colistin IV, metronidazole, tinidazole,        fusidic acid and trimethoprim; 2-thiopyridine N-oxide; halogen        compounds, particularly iodine and iodine compounds such as        iodine-PVP complex and diiodohydroxyquin; hexachlorophene;        chlorhexidine; chloroamine compounds; benzoylperoxide-   (z) Anti-tuberculosis drugs such as ethambutol, isoniazid,    pyrazinamide, rifampicin and clofazimine. Antimalarials such as    primaquine, pyrimethamine, chloroquine, hydroxychloroquine, quinine,    mefloquine and halofantrine.-   (aa) Antiviral agents such as acyclovir and acyclovir prodrugs,    famciclovir, zidovudine, didanosine, stavudine, lamivudine,    zalcitabine, saquinavir, indinavir, ritonavir, n-docosanol,    tromantadine and idoxuridine.-   (ab) Anthelmintics such as mebendazole, thiabendazole, niclosamide,    praziquantel, pyrantel embonate and diethylcarbamazine.-   (ac) Cytotoxic agents such as plicamycin, cyclophosphamide,    dacarbazine, fluorouracil and its prodrugs [described, for example,    in International Journal of Pharmaceutics 111, 223-233 (1994)],    methotrexate, procarbazine, 6-mercaptopurine and mucophenolic acid.-   (ad) Metabolism agents including anorectic and weight reducing    agents such as dexfenfluramine, fenfluramine, diethylpropion,    mazindol and phentermine.-   (ae) Agents used in hypercalcaemia such as calcitriol,    dihydrotachysterol and their active derivatives or analogs.-   (af) Respiratory System agents including:    -   (i) antitussives such as ethylmorphine, dextromethorphan and        pholcodine;    -   (ii) expectorants such as acetylcysteine, bromhexine, emetine,        guaiphenesin, ipecacuanha and saponins;    -   (iii) decongestants such as phenylephrine, phenylpropanolamine        and pseudoephedrine; and    -   (iv) bronchospasm relaxants such as ephedrine, fenoterol,        orciprenaline, rimiterol, salbutamol, tulobuterol, sodium        cromoglycate, cromoglycic acid and its prodrugs [described, for        example, in International Journal of Pharmaceutics 7, 63-75        (1980)], terbutaline, ipratropium bromide, salmeterol and        theophylline and theophylline derivatives.-   (ag) Allergy and Immune System agents including:    -   (i) antihistamines such as meclozine, cyclizine, chlorcyclizine,        hydroxyzine, brompheniramine, chlorpheniramine, clemastine,        cyproheptadine, dexchlorpheniramine, diphenhydramine,        diphenylamine, doxylamine, mebhydrolin, pheniramine,        tripolidine, azatadine, diphenylpyraline, methdilazine,        terfenadine, astemizole, loratidine and cetirizine.-   (ah) Local anaesthetics such as bupivacaine, amethocaine,    lignocaine, cinchocaine, dibucaine, mepivacaine, prilocaine and    etidocaine.-   (ai) Stratum corneum lipids, such as ceramides, cholesterol and free    fatty acids, for improved skin barrier repair [Man, et al. J.    Invest. Dermatol., 106(5), 1096, 1996].-   (aj) Neuromuscular blocking agents such as suxamethonium,    alcuronium, pancuronium, atracurium, gallamine, tubocurarine and    vecuronium.-   (ak) Smoking cessation agents such as nicotine, bupropion and    ibogaine.-   (al) Insecticides and other pesticides which are suitable for local    or systemic application.-   (am) Dermatological agents, such as vitamins A and E, vitamin E    acetate and vitamin E sorbate.-   (an) Allergens for desensitisation such as house dust mite allergen.-   (ao) Nutritional agents, such as vitamins, essential amino acids and    essential fats.-   (ap) Keratolytics such as the alpha-hydroxy acids, glycollic acid    and salicylic acid.-   (aq) Psychicenergisers, such as 3-(2-aminopropyl)indole,    3-(2-aminobutyl)indole, and the like.-   (ar) Anti-acne agents such as containing isotretinoin, tretinoin and    benzoyl peroxide.-   (as) Anti-psoriasis agents such as containing etretinate,    cyclosporin and calcipotriol.-   (at) Anti-itch agents such as capsaicin and its derivatives such as    nonivamide [Tsai, et al. Drug. Dev. Ind. Pharm., 20(4), 719, 1994].-   (au) Anticholinergic agents, which are effective for the inhibition    of axillary sweating and for the control of prickly heat. The    antiperspirant activity of agents such as methatropine nitrate,    propantheline bromide, scopolamine, methscopolamine bromide, and the    new class of soft antiperspirants, quaternary acyloxymethyl ammonium    salts [described, for example, by Bodor et al, J. Med. chem. 23,    474 (1980) and also in United Kingdom Specification No. 2010270,    published Jun. 27, 1979].-   (av) Other physiologically active peptides and proteins, small to    medium-sized peptides, e.g., vasopressin and human growth hormone.

Preferably the active agents are androgens, preferably testosterone;oestrogens, preferably estradiol; progesterone and other progestagens;broncho-dilators; anti-anxiety agents, preferably buspirone; and centralnervous system agents, preferably fentanyl.

In another embodiment, the composition may further include a secondactive agent to provide the composition with additional usage benefits.The second active agent may be any one of those listed above, or herbalextracts and/or cosmetic agents (such as, age spot and keratose removingagents, anti-aging agents, antioxidants, and hydroxy acids).

Preferably the second active agent is an antifungal agent. Fungalinfections are common in areas of the body having higher production ofheat and perspiration.

In yet another embodiment, the composition may further comprise one ormore inactive agents. Such inactive ingredients may be referred to as“additives”. Examples of such additives include but are not limited to,humectants, deodorant agents, antiperspirants, pH adjusting agents,preservatives, emulsifiers, occlusive agents (including withoutlimitation patches and film formers), solubilizing agents, colorants,and surfactants (including without limitation anionic surfactants).

The method of the invention is particularly suited to treatment oftestosterone insufficiency and the conditions and diseases associatedtherewith.

The invention may be applied to a range of active agents and in thetreatment of a range of conditions. These include the delivery ofoestradiol, progestin, ADHD agents and fentanyl, which may be used totreat various indications as already known by treatment through otherroutes of administration.

The preferred method of the invention wherein the active agent istestosterone or a derivative thereof, may be used to treat testosteronedeficiency in men and women and the conditions and diseases resultingtherefrom. The composition may comprise testosterone or a derivativethereof. There are number of closely related androgenic compounds whichare synthetically derivatized from testosterone are known to provide thesame or a similar physiologic activity, as discussed above.

Testosterone production in both men and women declines naturally withage. Testosterone deficiency may result from disease or damage to thehypothalamus, pituitary gland, or testicles that inhibits hormonesecretion and testosterone production, and is also known ashypogonadism. Depending on age, insufficient testosterone production canlead to abnormalities in muscle and bone development, underdevelopedgenitalia, and diminished virility, libido and/or desire.

Testosterone deficiency in men (hypogonadism) may be present at birth(congenital) or may develop later (acquired). It is classified by thelocation of its cause along the hypothalamic-pituitary-gonadal axis:

-   -   Primary, disruption in the testicles    -   Secondary, disruption in the pituitary    -   Tertiary, disruption in the hypothalamus.

The most common congenital cause is Klinefelter's syndrome. Thiscondition, which is caused by an extra X chromosome, results ininfertility, sparse facial and body hair, abnormal breast enlargement(gynecomastia), and small testes.

Congenital hormonal disorders such as leutenizing hormone-releasinghormone (LHRH) deficiency and gonadotropin-releasing hormone (GnRH)deficiency (e.g., Kallmann's syndrome) also may cause testosteronedeficiency.

Other congenital causes include absence of the testes (anorchism; alsomay be acquired) and failure of the testicles to descend into thescrotum (cryptorchidism).

Acquired causes of testosterone deficiency include chemotherapy; damageoccurring during surgery involving the pituitary gland, hypothalamus, ortestes; glandular malformation; head trauma that affects thehypothalamus; infection (e.g., meningitis, syphilis, mumps); isolated LHdeficiency (e.g., fertile eunuch syndrome); radiation; testiculartrauma; and tumours of the pituitary gland, hypothalamus, or testicles.

Androgen deficiency in women has been associated with an increased rateof sexual problems or complaints in a number of studies. These problemsare frequently encountered in oophorectomized women and those withandrogen deficiency from other causes. Hypoactive sexual desire disorder(HSDD) in women is the persistent or recurring deficiency (or absence)of sexual fantasies, thoughts and/or desire for, or receptivity to,sexual activity, which causes personal distress. The cause may be eitherphysiological or psychological or a combination of both. Commonphysiological etiologies include hormone deficiencies, medications, andsurgical interventions. Any disruption of the female hormonal milieucaused by these etiologies can result in decreased sexual desire. Thelack of, or a decrease in, sexual desire may also be secondary to poorsexual arousal and response, or to pain associated with sexual activity.Another factor may be difficulty with inability to attain or maintainsufficient sexual excitement, a condition known as female sexual arousaldisorder (FSAD).

The method of the invention may also be used in treatment of sexualdysfunction in men and women.

Normal daily production of testosterone in normal young men ranges from3-10 mg per day with diurnal variation (maximum ˜7 am decliningthroughout the day). The aim of testosterone therapy in men is todeliver physiologic amounts of testosterone to the systemic circulationproducing serum testosterone levels within the normal range for healthymen (e.g. 300-1000 ng/dL or 10-35 nM).

Several clinical studies have demonstrated that in conditions such asfemale sexual dysfunction, testosterone administration, which is aimedat restoring testosterone levels to normal reproductive levels, iseffective in improving sexual function. The studies to date suggest thatsystemic administration of doses ranging from 150 μg to 300 μg a daywould be sufficient to return testosterone levels to mid- to highpremenopausal levels in androgen deficient women.

The invention may be used in treating a wide variety of conditionsresponsive to testosterone therapy such as hypogonadism (primary andsecondary), AIDS Wasting Syndrome, micropenis, somatopause, andropause,viropause, or androgen deficiency in adult males (ADAM), anaemia fromrenal dialysis or chronic kidney disease, benign prostatic hyperplasia,acne, diabetes, infertility, libido, periodontal disease, post-anabolicsteroid abuse, dry eyes, diabetic retinopathy, retinopathy, and LupusErythematosis decreased bone density (i.e. osteoporosis), hyperlipemia,predisposition toward prostrate cancer, heart disease, angina, andhypertension.

When the composition of the invention and the composition used in themethod of the invention includes a volatile solvent, one of thesignificant advantages of the preferred embodiment of the invention isthat it dries rapidly, allows absorption of the active agent(particularly testosterone), and avoids the problems of accidentallydosing others by confining administration to axilla. The transdermalcomposition of the invention and the composition used in accordance withthe method of the invention do not interfere with the application anduse of other substances or products on the skin of a subject.

In the most preferred embodiment, the transdermal composition of theinvention and the composition used in the method of the invention isapplied as a lotion, spray or aerosol which is formulated to dry on theskin within three minutes of application. In this way we have found thatthe composition is driven into the skin and the testosterone compositionforms a reservoir in the skin which we have found is particularly activein enhancing blood levels via the axilla without the undesirable effectsassociated with high localised subcutaneous testosterone levels in thisregion.

The compositions used in the method of the invention preferably have adrying time of less than three minutes. Drying time may be determined byin vitro or in vivo tests. A suitable in vitro test involves placing a10 μL sample on a clean glass slide at room temperature (approx 20° C.)and using a four decimal place analytical balance the time take for thevehicle to stop evaporating is measured. The resulting drying times fromthree repetitions of the test may be averaged.

For in vivo drying time measurement 10 μLs applied to volar forearms(32° C.) of three subjects and the drying time is measured by touch andvisual verification (no visible surface vehicle or shine).

The invention will now be described with reference to the followingexamples. It is to be understood that the examples are provided by wayof illustration of the invention and that they are in no way limiting tothe scope of the invention.

EXAMPLES

The examples are described with reference to the drawings.

Example 1

This example compares the single dose pharmacokinetics of testosteronefollowing application of a single dose of a metered dose of atestosterone lotion to (a) the inner arm and (b) axilla, in healthywomen.

In this example, the composition (referred to here as “Composition 1”)contained the following components in the amounts by weight specified.

TABLE 1 Component Use Concentration Testosterone USP Active 1% w/v %Octisalate USP Penetration enhancer 8% w/v Povidone USP Thickener 1-5w/v % Purified water USP Vehicle 10% v/v Isopropyl alcohol USP Vehicle30% v/v Alcohol USP Vehicle balance

An open label, two period study was conducted in 12 healthypremenopausal women.

In each period, 1 mL of a metered dose testosterone lotion was appliedas a single dose to either the inner arm or the axilla according to therandomisation schedule. Samples were collected over 72 hours for eachsubject and subsequently analysed for testosterone content.

Two women were withdrawn from the study prior to the first dosingperiod. Ten women completed the study and the results are presented inthe graph shown in FIG. 1. The baseline corrected data comparingtestosterone uptake from the axilla and the inner arm shows that theaxilla has roughly a two fold increased uptake over the inner arm(AUC₀₋₇₂ was 5610.34 ng/dL/hr for the axilla compared to 2975.08ng/dL/hr for the inner arm). No adverse sweating or odour was reported.

Example 2

This example investigated the cumulative testosterone permeation throughhuman skin in vitro following deodorant spray application.

Finite-dose in vitro diffusion studies were undertaken using excisedhuman, male abdominal skin whereby the deodorant was applied to the skinsurface at pre-determined times after the topical application of a 5 μLdose of a testosterone lotion, formulated according to example 1. Theseexperiments were performed over 24 hours using stainless steel, flowthrough diffusion cells based on those described previously (Cooper, E.R. J. Pharm. Sci. 1984, 73, 1153-1156) except that the cell was modifiedto increase the diffusion area to 1.0 cm². The formulations were appliedusing a finite dose technique (Franz, T. J. Curr. Probl. Dermatol.,1978, 7, 58-68) to mimic clinical dosing conditions at an applied dosevolume of 5 μL/cm². A piece of stainless steel wire mesh was placeddirectly below the skin in the receptor chamber of the of the diffusioncell to maintain a turbulent flow of receptor solution below the skin.The diffusion cells were maintained at a flow rate of approximately 1.0mL/cm²/hr by a microcassette peristaltic pump (Watson Marlow 505S UK).The cells were kept at 32±0.5° C. by a heater bar and the samples werecollected into appropriately sized plastic vials on an automatedfraction collector (Isco Retriever II, Lincoln, Nebr.) at specifiedintervals. The receptor solution (20% v/v EtOH in 0.002% w/v NaN₃)maintained sink conditions below the skin.

At designated, pre-determined time points following the application ofthe testosterone lotion, the following were applied:

-   -   one spray of a deodorant (containing isobutane, denatured        alcohol, propane, triethyl citrate, parfum, butane, and water)        was applied to the skin surface for approximately 1 sec from a        constant distance of ˜10 cm from the top of the donor        compartment of the cell; or    -   3 μL of ethanol (the estimated amount of ethanol present in a 1        sec spray of deodorant).

The amount of testosterone that permeated the skin was quantified usinga validated HPLC method.

The application of a spray of deodorant at different time points afterthe topical application of the testosterone lotion did not have asignificant effect (enhancing or inhibitory) on the permeation oftestosterone through human epidermis in vitro. Application of neatethanol (EtOH) after testosterone lotion dosing also revealed nosignificant effect on the permeation of testosterone lotion throughhuman epidermis in vitro.

FIG. 2 shows the testosterone permeation profiles obtained afterapplication of deodorant spray to the formulation. FIG. 3 showstestosterone permeation profiles obtained after application of ethanol(3 μL) to the Composition 1 formulation. In both cases, it can be seenthat the control line does not differ significantly along the timeperiod examined.

The application of either a spray of deodorant or a finite-dose of neatEtOH did not appear to have an effect on the skin permeation oftestosterone from a 5 μL dose of the lotion. Therefore it was concludedthat the application of deodorant to the skin after application of thetestosterone lotion will not impede transdermal penetration oftestosterone.

Example 3

This example investigated the cumulative testosterone and estradiolpermeation through human skin in vitro when included in a commercialdeodorant

Finite-dose in vitro diffusion studies were undertaken usingheat-separated human, female abdominal epidermis. These experiments wereperformed over 24 hours using stainless steel, flow through diffusioncells based on those described previously (Cooper, E. R. J. Pharm. Sci.1984, 73, 1153-1156) except that the cell was modified to increase thediffusion area to 1.0 cm². The formulations were applied using a finitedose technique (Franz, T. J. Curr. Probl. Dermatol., 1978, 7, 58-68) tomimic clinical dosing conditions at an applied dose volume of 5 μL/cm².A piece of stainless steel wire mesh was placed directly below the skinin the receptor chamber of the of the diffusion cell to maintain aturbulent flow of receptor solution below the skin. The diffusion cellswere maintained at a flow rate of approximately 1.0 mL/cm²/hr by amicrocassette peristaltic pump (Watson Marlow 505S UK). The cells werekept at 32±0.5° C. by a heater bar and the samples were collected intoappropriately sized plastic vials on an automated fraction collector(Isco Retriever II, Lincoln, Nebr.) at specified intervals. The receptorsolution (20% v/v EtOH in 0.002% w/v NaN₃) maintained sink conditionsbelow the skin.

-   -   Two formulations were used that consisted of:        -   Composition 2: 1% w/v testosterone, 5% w/v octisalate, 32%            v/v EtOH to 100% v/v Deodorant (Rexona Essentials for Men            ‘Dry’ Antiperspirant Deodorant Spray, Unilever, Australia,            BN: 6030 10793)        -   Composition 3: 0.5% w/v E2 estradiol, 5% w/v octisalate, 52%            v/v EtOH to 100% v/v Deodorant (Rexona Activreserve ‘Classic            Silk’ Antiperspirant Deodorant Spray, Unilever, Australia,            BN: 6054 11280)    -   Note: extra ethanol was required in each of the formulations in        order for the octisalate to remain miscible. The amount of        ethanol differed between formulations as the deodorants used        differed.

The amount of testosterone (TES) and estradiol (E2) that permeated theskin was quantified using a HPLC method.

The permeation of TES through human epidermis in vitro was unalteredwhen the drug was added, with octisalate (OS) in an EtOH solution, to acommercial deodorant compared to its permeation from an ethanolicsolution without the penetration enhancer. FIG. 4 shows the TESpermeation profiles obtained from the application of Composition 2compared with application of a control. There is no significantdifference in the curves produced. With composition 3, the permeation ofE2 through human epidermis in vitro was significantly improved, when thedrug was added, with OS in an EtOH solution, to a commercial deodorantcompared to its permeation from an ethanolic solution without thepenetration enhancer. FIG. 5 shows the E2 permeation profiles obtainedfrom the application of Composition 3, compared with application of acontrol. The improved permeation is apparent after only 4 hours, and thedifference becomes more significant with time particularly after 16hours from dose.

The in vitro skin permeation of TES or E2 from an ethanolic solutioncomprised of OS and a commercial deodorant was therefore comparable to,if not higher than, its permeation from the ethanolic solutionscomprised of the drug alone. This demonstrates that the addition ofingredients typically found in commercial deodorants to the formulationsdid not inhibit transdermal permeation of testosterone or estradiol.

Example 4

A study was conducted to assess the antiperspirant and deodorantcharacteristics of Composition 1 without added antiperspirant ordeodorants. In this study, 16 male volunteers were asked to applyComposition 1 to their axilla(s) in a similar manner as in Example 1,and also to refrain from the use of other deodorants or antiperspirantson the axilla (armpits) that received Composition 1. The subjects were,however, instructed to apply deodorant if they were distressed withsymptoms of sweating and to report such application. Interestingly, noneof the subjects reported a need to use deodorant or antiperspirant whenComposition 1 had been applied to the axilla.

Finally, various other modifications and/or alterations may be madewithout departing from the spirit of the present invention as outlinedherein. The invention disclosed and defined in this specificationextends to all alternative combinations of two or more of the individualfeatures mentioned or evident from the text or drawings. All of thesedifferent combinations constitute various different aspects of theinvention.

The invention claimed is:
 1. A method of increasing the testosteroneblood level of an adult male subject in need thereof comprising applyingto at least one axilla of the subject, without occlusion by a patchdevice, a non-occlusive transdermal drug delivery composition consistingof: (a) a pharmaceutically effective amount of testosterone; (b) one ormore lower alkyl alcohols, wherein the combined volume of the loweralkyl alcohols is more than 60% (v/v) of the composition; (c) one ormore penetration enhancers selected from the group consisting ofglycols, oleic acid, isopropyl myristate, cyclopentadecanone, sorbitanmonooleate, octisalate, octyldimethyl-para-aminobenzoate, octylpara-methoxycinnamate, and combinations thereof; (d) one or moreviscosity modulating agents; (e) optionally, an activator for theviscosity modulating agent; (f) optionally, an antiperspirant and/ordeodorant agent; and (g) optionally, water wherein the composition isapplied in an amount effective to achieve a testosterone blood level inthe subject of at least 200 ng/dL.
 2. The method of claim 1, wherein theadult male subject is suffering from androgen deficiency.
 3. The methodof claim 1, wherein the lower alkyl alcohol is selected from the groupconsisting of ethanol, isopropanol, and mixtures thereof, and whereinthe combined volume of the lower alkyl alcohol(s) is more than 70% (v/v)of the composition.
 4. The method of claim 3, wherein the combinedvolume of lower alkyl alcohol(s) is more than 80% (v/v) of thecomposition.
 5. The method of claim 1, wherein the penetration enhanceris one or more selected from the group consisting of octyldimethyl-para-aminobenzoate, octyl para-methoxycinnamate and octisalate.6. The method of claim 1, wherein the penetration enhancer isoctisalate.
 7. The method of claim 1, wherein the viscosity modulatingagent is selected from the group consisting of polyvinyl pyrrolidone andhydroxypropyl methyl cellulose.
 8. The method of claim 1, wherein theviscosity modulating agent is polyvinyl pyrrolidone and is present in anamount of from 1% to 3% (w/v) of the composition.
 9. The method of claim1, wherein the amount of viscosity modulating agent is effective toincrease the viscosity of the composition to within the range of fromgreater than the viscosity of water to less than 300 centipoise.
 10. Themethod of claim 1, wherein the penetration enhancer is present in anamount of from 0.01 to 15% (w/v) of the composition.
 11. The method ofclaim 1, wherein the penetration enhancer is isopropyl myristate. 12.The method of claim 11, wherein the lower alkyl alcohol is selected fromthe group consisting of ethanol, isopropanol, and mixtures thereof, andwherein the combined volume of lower alkyl alcohol(s) is more than 70%(v/v) of the composition.
 13. A method of increasing the testosteroneblood level of an adult male subject in need thereof comprising applyingto at least one axilla of the subject, without occlusion by a patchdevice, a non-occlusive transdermal drug delivery composition consistingof: (a) a pharmaceutically effective amount of testosterone; (b) one ormore lower alkyl alcohols, wherein the combined volume of the loweralkyl alcohol(s) is more than 60% (v/v) of the composition; (c) one ormore penetration enhancers selected from the group consisting ofoctisalate, octyldimethyl-para-aminobenzoate and octylpara-methoxycinnamate; (d) one or more viscosity modulating agents, inan amount effective to increase the viscosity of the composition towithin the range of from greater than the viscosity of water to lessthan 300 centipoise; and (e) optionally, water wherein the compositionis applied in an amount effective to achieve a testosterone blood levelin the subject of at least 200 ng/dL.
 14. The method of claim 13 whereinthe penetration enhancer is present in an amount of from 0.01% to 15%(w/v) of the composition.
 15. The method of claim 14 wherein thepenetration enhancer is octisalate.
 16. The method of claim 15, whereinthe lower alkyl alcohol is selected from the group consisting ofethanol, isopropanol, and mixtures thereof.
 17. The method of claim 16wherein the combined volume of lower alkyl alcohol(s) is more than 70%(v/v).
 18. The method of claim 17 wherein the combined volume of loweralkyl alcohols(s) is more than 80% (v/v).
 19. The method of claim 18wherein the viscosity modulating agent is polyvinyl pyrrolidone.
 20. Themethod of claim 19 wherein the polyvinyl pyrrolidone is present in anamount of from 1% to 3% (w/v) of the composition.
 21. The method ofclaim 13, wherein the adult male subject is suffering from androgendeficiency.